: Viral vectors genetically-engineered for replication restricted to cancer cells represent an attractive strategy for prostate cancer therapy because these viruses can replicate and spread in the tumor yet be non-toxic to normal prostate and the surrounding nerves. This overcomes a current challenge of conventional treatments, such as surgery and radiation therapy, and has opened a new avenue for cancer therapy - viral oncolysis- which allows for methods of tumor cell killing that are unique in the field of cancer therapy. Since the mechanisms of viral therapy and the potential toxicities differ from those of standard hormonal or chemotherapy, the possibilities of synergy are worthy of exploration. We have provided data leading to a paradigm shift in thinking about the interactions of pharmaceuticals and/or small molecules with cancer cell pathways and specific oncolytic herpes simplex virus (oHSV) gene mutations. Our overarching hypothesis is that we can identify specific pharmaceuticals and/or small molecules that modulate important prostate cancer cell pathways and, when paired with appropriate oHSV vectors can increase oncolytic cancer cell destruction. We plan to study the following aims: AIM 1: We hypothesize that the small molecules identified by our high throughput screen to enhance oHSV spread in human prostate cancer cells, will synergize in vitro and in vivo to kill prostate cancer; AIM 2: We hypothesize that histone deacetylase inhibitors will sensitize prostate cancer cells to oHSV bearing appropriate mutations through effects on oncogenic signaling pathways; AIM 3: We hypothesize that oHSV's can act as antiangiogenic vectors by attenuating the expression of proangiogenic factors induced by hypoxia and that this effect can be further enhanced by microtubule-spindle poisons. PUBLIC HEALTH RELEVANCE: Current treatment modalities for localized prostate cancer include surgery and radiation therapy, both of which are associated with risks of nerve damage and sexual and/or bladder dysfunction, and other complications. Metastatic prostate cancer also has poor treatment options. In this proposal, we are developing therapeutic modalities to target both local and metastatic disease. This and the lack of good chemotherapeutic responses underscores the public health relevance and importance of developing our proposed strategy as a novel approach to the critical problem of prostate cancer therapy.